[unreadable] [unreadable] Esophageal adenocarcinoma is an insidious disease that is frequently diagnosed at late stage when treatment is ineffective. As a result, most patients die within 12 months of diagnosis and the long term survival rate is extremely poor. When diagnosed early however, surgery can be very effective with cure rates as high as 80%. The incidence of esophageal adenocarcinoma is increasing rapidly in the United States (U.S.) and other Westernized countries at a rate surpassing that of any other tumor type. A likely explanation for this phenomenon is the current epidemic of obesity in the U.S. and its association with gastroesophageal reflux disease (GERD) which is a strong risk factor for development of esophageal adenocarcinoma. Chronic reflux exposes the distal esophagus to stomach acid and bile causing irritation and inflammation. In some patients, this leads to the development of premalignant intestinal metaplasia, otherwise known as Barrett's esophagus. Esophageal adenocarcinoma is believed to originate from this metaplasia via progression through low grade dysplasia to high grade dysplasia and on to adenocarcinoma. Esophagectomy is often recommended for patients with high grade dysplasia but this is somewhat controversial with some clinicians preferring frequent surveillance rather than surgery. Additional tools are required to identify patients at risk for disease progression and who may therefore benefit from the most aggressive treatment. We hypothesize that expression of micro RNA may provide molecular markers of progression and we will test this hypothesis in Specific Aim 1 of this proposal. Another surgical dilemma in the treatment of esophageal cancer arises in patients with adenocarcinoma that spans the gastroesophageal junction (GEJ). In many cases, it is unclear whether the tumor arose in the distal esophagus or in the cardia of the stomach. This is an important distinction since staging schemes, treatment modalities and surgical procedures are all impacted by probable site of origin. Unfortunately, histologic and current molecular analyses cannot differentiate between esophageal adenocarcinoma and adenocarcinoma of the gastric cardia. Micro RNA expression profiles appear to be an extremely good indicator of tumor origin and therefore, we hypothesize that analysis of micro RNA expression in tumors of the GEJ will provide accurate classification where other approaches have failed. This hypothesis will be tested in Specific Aim 2. Together the Specific Aims in this proposal have strong clinical relevance for the treatment of esophageal adenocarcinoma; a disease which continues to rise rapidly in incidence in the U.S. and has a generally poor outcome unless diagnosed early. Identification of unique miRNA profiles should be useful in molecular classification of premalignant esophageal lesions and GEJ adenocarcinomas and thus improve the current surgical treatment and outcome from this deadly disease. [unreadable] [unreadable] [unreadable] [unreadable]